Department of Physiology, School of Medicine-CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela (A Coruña) 15782, Spain.
J Pathol. 2012 Jun;227(2):209-22. doi: 10.1002/path.3984. Epub 2012 Feb 17.
Hyperthyroidism is characterized in rats by increased energy expenditure and marked hyperphagia. Alterations of thermogenesis linked to hyperthyroidism are associated with dysregulation of hypothalamic AMPK and fatty acid metabolism; however, the central mechanisms mediating hyperthyroidism-induced hyperphagia remain largely unclear. Here, we demonstrate that hyperthyroid rats exhibit marked up-regulation of the hypothalamic mammalian target of rapamycin (mTOR) signalling pathway associated with increased mRNA levels of agouti-related protein (AgRP) and neuropeptide Y (NPY), and decreased mRNA levels of pro-opiomelanocortin (POMC) in the arcuate nucleus of the hypothalamus (ARC), an area where mTOR co-localizes with thyroid hormone receptor-α (TRα). Central administration of thyroid hormone (T3) or genetic activation of thyroid hormone signalling in the ARC recapitulated hyperthyroidism effects on feeding and the mTOR pathway. In turn, central inhibition of mTOR signalling with rapamycin in hyperthyroid rats reversed hyperphagia and normalized the expression of ARC-derived neuropeptides, resulting in substantial body weight loss. The data indicate that in the hyperthyroid state, increased feeding is associated with thyroid hormone-induced up-regulation of mTOR signalling. Furthermore, our findings that different neuronal modulations influence food intake and energy expenditure in hyperthyroidism pave the way for a more rational design of specific and selective therapeutic compounds aimed at reversing the metabolic consequences of this disease.
甲状腺功能亢进症的特征是能量消耗增加和明显的多食。与甲状腺功能亢进相关的产热改变与下丘脑 AMPK 和脂肪酸代谢的失调有关；然而，介导甲状腺功能亢进引起的多食的中枢机制在很大程度上仍不清楚。在这里，我们证明甲状腺功能亢进的大鼠表现出明显的下丘脑哺乳动物雷帕霉素靶蛋白（mTOR）信号通路的上调，与下丘脑弓状核（ARC）中 AgRP 和神经肽 Y（NPY）的 mRNA 水平增加以及 pro-opiomelanocortin（POMC）的 mRNA 水平降低有关，mTOR 与甲状腺激素受体-α（TRα）在该区域共定位。ARC 中甲状腺激素（T3）的中枢给药或甲状腺激素信号的遗传激活再现了甲状腺功能亢进对摄食和 mTOR 途径的影响。反过来，用 rapamycin 对甲状腺功能亢进大鼠进行中枢抑制 mTOR 信号，可逆转多食并使 ARC 衍生神经肽的表达正常化，导致体重显著减轻。这些数据表明，在甲状腺功能亢进状态下，摄食增加与甲状腺激素诱导的 mTOR 信号上调有关。此外，我们的发现表明，不同的神经元调节影响甲状腺功能亢进症中的摄食和能量消耗，为设计旨在逆转这种疾病代谢后果的特异性和选择性治疗化合物开辟了道路。
